Concentration-dependent antagonism and culture conversion in pulmonary tuberculosis. Rockwood, N., Pasipanodya, J. G, Denti, P., Sirgel, F., Lesosky, M., Gumbo, T., Meintjes, G. A, McIlleron, H., & Wilkinson, R. J Clinical Infectious Diseases, 64(10):1350–1359, 2017. ![Concentration-dependent antagonism and culture conversion in pulmonary tuberculosis [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.One hundred patients with pulmonary tuberculosis (65$\$$\$% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7–8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5–6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC ($\$$\$%TMIC).Twenty-six percent of patients had Cmax of rifampicin $\$$\$\textless8 mg/L, pyrazinamide $\$$\$\textless35 mg/L, and isoniazid $\$$\$\textless3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was $\$$\$\textless4.6 mg/L and rifampicin Cmax/MIC $\$$\$\textless28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax $\$$\$\textgreater4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.
@article{10.1093/cid/cix158,
abstract = {There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.One hundred patients with pulmonary tuberculosis (65$\backslash$$\backslash${\%} human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7–8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5–6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC ($\backslash$$\backslash${\%}TMIC).Twenty-six percent of patients had Cmax of rifampicin $\backslash$$\backslash${\textless}8 mg/L, pyrazinamide $\backslash$$\backslash${\textless}35 mg/L, and isoniazid $\backslash$$\backslash${\textless}3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was $\backslash$$\backslash${\textless}4.6 mg/L and rifampicin Cmax/MIC $\backslash$$\backslash${\textless}28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax $\backslash$$\backslash${\textgreater}4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.},
author = {Rockwood, Neesha and Pasipanodya, Jotam G and Denti, Paolo and Sirgel, Frederick and Lesosky, Maia and Gumbo, Tawanda and Meintjes, Graeme A and McIlleron, Helen and Wilkinson, Robert J},
doi = {10.1093/cid/cix158},
issn = {1058-4838},
journal = {Clinical Infectious Diseases},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
number = {10},
pages = {1350--1359},
pmid = {28205671},
title = {{Concentration-dependent antagonism and culture conversion in pulmonary tuberculosis}},
url = {https://doi.org/10.1093/cid/cix158},
volume = {64},
year = {2017}
}
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Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5–6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC ($\\$$\\$%TMIC).Twenty-six percent of patients had Cmax of rifampicin $\\$$\\$\\textless8 mg/L, pyrazinamide $\\$$\\$\\textless35 mg/L, and isoniazid $\\$$\\$\\textless3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was $\\$$\\$\\textless4.6 mg/L and rifampicin Cmax/MIC $\\$$\\$\\textless28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax $\\$$\\$\\textgreater4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.","author":[{"propositions":[],"lastnames":["Rockwood"],"firstnames":["Neesha"],"suffixes":[]},{"propositions":[],"lastnames":["Pasipanodya"],"firstnames":["Jotam","G"],"suffixes":[]},{"propositions":[],"lastnames":["Denti"],"firstnames":["Paolo"],"suffixes":[]},{"propositions":[],"lastnames":["Sirgel"],"firstnames":["Frederick"],"suffixes":[]},{"propositions":[],"lastnames":["Lesosky"],"firstnames":["Maia"],"suffixes":[]},{"propositions":[],"lastnames":["Gumbo"],"firstnames":["Tawanda"],"suffixes":[]},{"propositions":[],"lastnames":["Meintjes"],"firstnames":["Graeme","A"],"suffixes":[]},{"propositions":[],"lastnames":["McIlleron"],"firstnames":["Helen"],"suffixes":[]},{"propositions":[],"lastnames":["Wilkinson"],"firstnames":["Robert","J"],"suffixes":[]}],"doi":"10.1093/cid/cix158","issn":"1058-4838","journal":"Clinical Infectious Diseases","keywords":"OA,fund_not_ack,original","mendeley-tags":"OA,fund_not_ack,original","number":"10","pages":"1350–1359","pmid":"28205671","title":"Concentration-dependent antagonism and culture conversion in pulmonary tuberculosis","url":"https://doi.org/10.1093/cid/cix158","volume":"64","year":"2017","bibtex":"@article{10.1093/cid/cix158,\r\nabstract = {There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.One hundred patients with pulmonary tuberculosis (65$\\backslash$$\\backslash${\\%} human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7–8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5–6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. 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